Advances in genomic and proteomic studies continue to reveal new targets for therapeutic intervention. The identification of ligands for such targets remains a major opportunity and challenge. To this end, a variety of target-oriented ligand-binding assays have been developed, including affinity selections on DNA-encoded chemical libraries,1,2 selection-like methods such as interaction-dependent PCR,3 and a wide variety of screening platforms.4 
Selections offer substantially improved throughput and decreased time, cost, and material consumption compared to screens, but generally rely on purified, heterologously expressed proteins in an artificial context that includes an immobilized1 or DNA-linked3 protein, the compound library, and buffer. Selections conducted in this manner can be incompatible with poorly soluble, aggregation-prone, difficult-to-purify, intrinsically disordered, or membrane-bound targets. Moreover, the results of selections on immobilized targets may lack biological relevance for proteins that adopt non-native conformations or lack binding partners or co-factors essential for their function when taken out of the cellular context.5 Although a number of successful selections have been conducted using purified proteins,1 increasing the biological relevance of selection methods will significantly increase their effectiveness.